Strict BP Control Helps Save Kids' Renal Function

Action Points

Explain to interested patients and parents that in this study strict blood pressure control to the low end of normal helped preserve kidney function in children with chronic renal disease.

Also explain that this study suggests that proteinuria may rebound even with good blood pressure control, and that additional therapeutic strategies may be needed.

Intensified blood pressure control conferred significant benefits on renal function in children with chronic kidney disease, a multicenter European study found.

Among patients treated with an intensified regimen that included a fixed high dose of ramipril, 29.9% reached the primary endpoint, a 50% reduction in glomerular filtration rate or progression to end-stage renal disease, an article in the Oct. 22 New England Journal of Medicine reported.

That compared with 41.7% of those who received conventional blood pressure control, according to Elke Wühl, MD, of the University of Heidelberg in Germany, and colleagues from the ESCAPE Trial Group.

The hazard ratio for progressing to this endpoint with blood pressure targeted to the low end of normal was 0.65 (95% CI 0.44 to 0.94, P=0.02), the investigators reported.

The trial was originally planned for three years, but when an interim analysis found that overall disease progression was less than expected, it was extended to five years.

All children received 6 mg/m2 per body surface area per day of the angiotensin-converting-enzyme (ACE) inhibitor ramipril, after gradual titration from 1.25 mg/m2 during the first two months of the study.

They were randomized to treatment of blood pressure using a conventional target (50th to 90th percentile) or to an intensified target (<50th percentile). Additional antihypertensives (excluding other renin-angiotensin system antagonists) were permitted after the first six months, as needed, to achieve the target.

The majority of patients had renal hypoplasia-dysplasia, but other underlying diagnoses included glomerulopathies and congenital or hereditary nephropathies.

During the course of the study, 46 of 182 patients in the intensified-control group and 69 of 190 in the conventional-control group progressed to the primary endpoint.

This corresponded to an actuarial five-year rate of delay in progression of 70.1%, compared with 58.3% (P=0.02), according to the researchers.

Covariates that were associated with increased risk of reaching the primary endpoint included:

Blood pressure decreased in both intensive- and conventional-control groups. The mean number of additional antihypertensives prescribed for patients in the intensified-control group and conventional control groups was 0.9 and 0.5, respectively.

Some 60% of patients in the intensified control group reached the target 24-hour mean arterial pressure (<50th percentile) at one year. At two years, 73% had reached the target; at five years, it was 74%.

In the standard-control group, the same target was reached by more than 50%, even with ramipril monotherapy.

On the endpoint of change in the glomerular filtration rate, there were no significant differences between the two groups.

Proteinuria initially fell by an average of 50% following the institution of ACE inhibitor therapy, from a median of 0.82 g protein/g creatinine to 0.36 g (P<0.001) during the first six months of the study. But by 36 months, levels had returned to baseline.

"We speculate that the late increase in proteinuria may be related to the 'aldosterone breakthrough' phenomenon, a condition that was recently reported to occur in up to 40% of adults receiving long-term ACE-inhibitor therapy," the investigators wrote.

That phenomenon may relate to up-regulation of other enzymes and vasoactive mediators, as well as an increase in excretion of endothelin-1. Or it may reflect the natural course of the underlying renal ailment, the investigators wrote.

Concerns about the proteinuria rebound were echoed by Julie R. Ingelfinger, MD, of Massachusetts General Hospital, in an accompanying editorial.

"Unexpectedly, the proteinuria in the participants initially decreased by half but then gradually increased, despite good blood-pressure control in both study groups," she wrote.

Therefore, the investigators said, "Follow-up strategies are needed to treat patients in whom secondary proteinuria that is resistant to ACE-inhibitor therapy develops."

Dr. Ingelfinger concluded, "One hopes that this study will set a precedent for long-term, randomized, controlled treatment trials involving children with renal disease."

ESCAPE was supported by grants from Boehringer Ingelheim Stiftung, the European Commission, Kuratorium fü Dialyse und Nierentransplantation, and the Baxter Extramural Grant Program.

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